This proposal tyrosine kinases and prostate cancer began in 1998 with the development of tyrosine kinase display approach and the first comprehensive tyrosine kinase profile of prostate cancer cells. In the ensuing years, tyrosine kinases involved in androgen independence were identified and the processes characterized. This led to the discovery of Src tyrosine kinase (TK) complex as a central integrator of signals emanating from tyrosine kinase receptor, cytokine receptor and G-protein coupled receptor. Recent studies from several labs including the PI's showed that Src activation is frequently found in castration resistant prostate cancer and Src signatures are found in most metastatic tumors including those which lack androgen receptor expression. The Src TK complex presents novel targets for potential therapeutic intervention. A number of Src inhibitors have entered clinical trials including one based on our study. However, as a monotherapy, Src-targeting therapy has met with limited success, and there is a need for improvement. In the past grant period, with an emphasis on translational research, we have focused on Src selective inhibitors as a potential therapy for prostate cancer and as a probe for critical src-mediated signal pathways involved in prostate cancer progression. We have made significant progress with the major discovery of autophagy as an underlying mechanism of prostate cancer cell's resistance to apoptosis induced by Src-targeting therapy. We also identified several signal pathways associated with Src-mediated prostate carcinogenesis. Built upon the progress made in the past three years, the present proposal continues to focus on the discovery of novel Src oncogenic pathway and the improvement of Src inhibitor-based therapy. Specifically, we will study a new signal pathway which connects Src to ERG via microRNA modulation and the improvement of Src targeting therapy by a combination of autophagy modulators.